Ma Jun, Qiu Jingjing, Wright Gus A, Wang Shiren
Department of Biomedical Engineering, Texas A&M University, College Station, Texas 77843, United States.
Department of Mechanical Engineering & Department of Materials Science and Engineering, Texas A&M University, College Station, Texas 77843, United States.
Mol Pharm. 2025 Jan 6;22(1):168-180. doi: 10.1021/acs.molpharmaceut.4c00817. Epub 2024 Nov 21.
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor, with a poor prognosis. Temozolomide (TMZ) represents the standard chemotherapy for GBM but has limited efficacy due to poor targeting and a hypoxic tumor microenvironment (TME). To address these challenges, we developed a dual-gas-releasing, cancer-cell-membrane-camouflaged nanoparticle to deliver TMZ. This nanoceria, camouflaged with a cancer cell membrane (CCM-CeO), targets explicitly GBM cells and accumulates in lysosomes, triggering the rapid release of TMZ. Additionally, CCM-CeO could release oxygen (O) and nitric oxide (NO) in response to the TME. Synthesized using d-arginine, catalytic nanoceria could decompose excessive hydrogen peroxide (HO) in the TME to produce O, while d-arginine could nonenzymatically react with HO to generate NO. CCM-CeO could penetrate GBM spheroids to a depth of 148.3 ± 31 μm, with the O and NO produced, reducing HIF-1α protein expression. When loaded with TMZ, CCM-CeO could increase the intracellular ROS produced by TMZ, leading to lysosome membrane permeabilization and notably augmented apoptosis and necrosis in GBM cells. An in vitro antitumor assay using spheroids showed that CCM-CeO reduced the IC value of TMZ from 174.5 to 42.6 μg/mL, likely due to the catalase-like activity of nanoceria. These results suggest that alleviating hypoxia and increasing ROS produced by chemotherapeutics could be an effective therapeutic strategy for treating GBM.
多形性胶质母细胞瘤（GBM）是最常见且侵袭性最强的恶性脑肿瘤，预后较差。替莫唑胺（TMZ）是GBM的标准化疗药物，但由于靶向性差和肿瘤微环境（TME）缺氧，其疗效有限。为应对这些挑战，我们开发了一种双气体释放、癌细胞膜伪装的纳米颗粒来递送TMZ。这种用癌细胞膜伪装的纳米氧化铈（CCM-CeO）能够明确靶向GBM细胞并在溶酶体中积累，从而触发TMZ的快速释放。此外，CCM-CeO可响应TME释放氧气（O）和一氧化氮（NO）。催化纳米氧化铈由d-精氨酸合成，可分解TME中过量的过氧化氢（HO）以产生O，而d-精氨酸可与HO非酶促反应生成NO。CCM-CeO可穿透GBM球体至148.3±31μm的深度，所产生的O和NO可降低缺氧诱导因子-1α（HIF-1α）蛋白表达。当负载TMZ时，CCM-CeO可增加TMZ产生的细胞内活性氧（ROS），导致溶酶体膜通透性增加，并显著增强GBM细胞的凋亡和坏死。使用球体进行的体外抗肿瘤试验表明，CCM-CeO将TMZ的半数抑制浓度（IC）值从174.5μg/mL降至42.6μg/mL，这可能归因于纳米氧化铈的过氧化氢酶样活性。这些结果表明，缓解缺氧并增加化疗药物产生的ROS可能是治疗GBM的有效治疗策略。
